The present invention relates to various indazoles and indoles. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma.
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
Serotonergic 5-HT1A agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke among other indications. This class of compounds has been mentioned for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.) and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol. 210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT) (a 5-HT1A agonist) reduces IOP in rabbits. Wang, et al. (Current Eye Research, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488, March, 1998) indicate that 5-methylurapidil, an α1A antagonist and 5-HT1A agonist lowers IOP in the monkey, but due to its alA receptor activity. Also, 5-HT1A antagonists are disclosed as being useful for the treatment of glaucoma (elevated IOP) (e.g., WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al. (U.S. Pat. No. 5,578,612) relate to the use of 5-HT1 and 5-HT1-like agonists for the treatment of glaucoma (elevated IOP). These anti-migraine compounds, e.g., sumatriptan and naratriptan and related compounds, are 5-HT1B,D,E,F agonists.
It has been found that serotonergic compounds which possess agonist activity at 5-HT2 receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888, incorporated in its entirety by reference herein. Compounds that act as agonists at 5-HT2 receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 relates to certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT2C agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 relates to tryptamine derivatives that are 5-HT2 agonists for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 relates to a method for treating malaria using 5-HT2A/2C agonists. U.S. Pat. No. 5,902,815 relates to the use of 5-HT2A agonists to prevent adverse effects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT2B agonists for the treatment of depression and other CNS conditions. WO 00/12475 relates to indoline derivatives and WO 00/12510 and WO 00/44753 relate to certain indole derivatives as 5-HT2B and 5-HT2C receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity. WO 00/35922 relates to certain pyrazino[1,2-a]quinoxaline derivates as 5-HT2C agonists for the treatment of obsessive compulsive disorder, depression, eating disorders, and other disorders involving the CNS.
WO 00/77002 and WO 00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indoles as 5-HT2C agonists with utility for the treatment of central nervous system disorders including obesity, anxiety, depression, sleep disorders, cephalic pain, and social phobias among others. Agonist response at the 5-HT2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT2C receptor possible [Psychopharmacology, Vol. 121:357, 1995].
U.S. Pat. Nos. 5,561,150 and 5,646,173 relate to certain tricyclic pyrazole derivative compounds which are identified as being 5-HT2C agonists for the treatment of CNS diseases and are primarily directed to lipophilic analogs that have a high probability of entering the brain. Similarly, WO 98/56768 relates to tricyclic 5-HT2C agonists for the treatment of CNS diseases. All the patents, patent applications, and publications mentioned above and throughout are incorporated in their entirety by reference herein and form a part of the present application.
5-Hyroxytryptamine (serotonin) does not cross the blood-brain barrier and enter the brain. However, in order to increase brain serotonin levels the administration of 5-hydroxytryptophan can be employed. The transport of 5-hydroxy-tryptophan into the brain readily occurs, and once in the brain 5-hydroxy-tryptophan is rapidly decarboxylated to provide serotonin.
The chemical synthesis of 2-(4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine has been reported [J. Heterocyclic Chem. 11, 387 (1974), Chem. Heterocycl. Compd. (Engl. Transl.) 9, 196 (1973)] with no mention of utility. The synthesis of selected 2-(4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine derivatives, such as 2-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethylamine, has been reported [Bioorg. Med. Chem. Lett. 10, 919 (2000)]. It was suggested that such compounds could have utility in the treatment of epilepsy and obesity. The preparation of 1- and 2-substituted 2H-indeno[1,2,3-cd]indazoles is disclosed in Belg. 718,057 (1968); these compounds are noted as having psychotherapeutic activity. Various ring substituted amides and esters of 7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinoline-2-carboxylic acid have been disclosed as antagonists at 5-HT3 receptors [U.S. Pat. No. 4,985,424].
Accordingly, there is a need to provide new compounds which avoid the disadvantages described above and which provide increased chemical stability and a desired length of therapeutic activity, for instance, in decreasing intraocular pressure and treating glaucoma.